Positive Allosteric Modulators (Pams) Of The Group Ii Metabotropic Glutamate Receptors: Design, Synthesis, And Evaluation As Ex-Vivo Tool Compounds

This letter describes synthesis and evaluation of two series of dual mGlu(2)/mGlu(3) positive allosteric modulators with moderate mGlu(3) potency and robust mGlu(2) potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu(3)-mediated signaling in central neurons by co-application of a selective mGlu(2) NAM to isolate mGlu(3)-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca2+ signaling in PFC pyramidal cells with either the dual mGlu(2)/mGlu(3) PAM 16e or 23d demonstrated effects mediated selectively via mGlu(3).